Reducing inflammation may lower the risk of dementia in RA

The incidence of dementia in patients with RA taking either a biologic disease-modifying antiretroviral (BDMARD) or a targeted synthetic DMARD (TSDMARD) was significantly lower than that observed in patients taking only a conventional synthetic DMARD (CSDMARD) in a to a in patients taking conventional synthetic DMARD National Database Study only.

The work builds on previous research that suggests a higher risk of Alzheimer’s disease and related dementias in people with RA. While joint pain and swelling are the cardiac hallmarks of RA, its systemic inflammation leads to multiple systemic symptoms, offering a biologically plausible link to cognitive decline. In addition, patients with RA have a high prevalence of cardiovascular disease, diabetes, depression, disability, and physical inactivity, all of which are risk factors for dementia.

Chronic neuroinflammation following either intrinsic or systemic stimuli is thought to play a key role in the development of dementia, particularly Alzheimer’s (AD). Studies showing the role of tumor necrosis factor-alpha (TNF-alpha) in the development of dementia have interested the potential protective effect of TNF inhibitors. “TNF-alpha is thought to have an important role at different stages of pathology and disease progression in Alzheimer’s disease,” says study first author Sebastian E. Sattui, MD, assistant professor of medicine at the University of Pittsburgh and director of the University of Pittsburgh Vascular Inflammation Center, said in an interview. “Animal models have shown that TNF inhibition reduces microglial, neuronal, and tau phosphorylation. Cognitive improvement has been observed in two studies in patients with Alzheimer’s disease, but not in patients with rheumatoid arthritis.”

In the latest study, published online in Symposium on Arthritis and Rheumatism, Sattui and colleagues suggest that the reduced risk of dementia seen with BDMARDS and TSDMARDS may be attributable to an overall greater reduction in inflammation rather than any specific mechanisms of action. these drugs.

In a 2006-2017 Centers for Medicare & Medicaid Services claims study of 141,326 adult patients with RA, the crude incidence rate was 2.0 per 100 person-years (95% confidence interval, 1.9-2.1) in patients with CSDMards and 1.3 (95% CI, 1.2-1.4) for patients on any B/TSDMARD. There were 3,794 cases of incident dementia during follow-up among 233,271 initiations of each DMARD. The adjusted risk for dementia among users of BDMARDS or TSDMARDS was 19% lower than the adjusted risk in patients on CSDMARDs (hazard ratio, 0.81; 95% CI, 0.76-0.87). No significant differences were found between categories of BDMARDS or TSDMARDS.

The study by Sattui and Coauthors included adults at least 40 years of age with two RA diagnoses by a rheumatologist more than 7 and less than 365 days apart. Those with previous diagnoses of dementia were excluded. Their analysis found that the risk of incident dementia was similar between patients receiving TNF inhibitors (HR, 0.86; 95% CI, 0.80-0.93), not TNFi BDMARDs (HR, 0.76; 95% CI , 0.70-0.83) and TSDMARDS (HR, 0.69; 95% CI, 0.53-0.90), with CSDMARDS as reference. Another subgroup analysis looking at patients with prior methotrexate use who were taking BDMARDs or TSDMARDS found a similar reduction in the risk of dementia, compared to patients taking BDMARDS or TSDMARDS plus methotrexate at baseline.

“NSAIDs and glucocorticoids have been studied in RCTs [randomized, controlled trials],” Sattui said in the interview. “Despite initial observational data showing some signs of improvement, no benefit was observed in either RCT. Other drugs with potential anti-inflammatory effects and benign profiles, such as curcumin, are being investigated. There are also ongoing trials looking at the use of Jak [Janus kinase] brakes or [interleukin]-1 inhibition in dementia. “

He added: “There is a need for further investigation of the relationship between cognition and disease activity, as well as treatment strategies, in patients with RA in the future.” It is important to also recognize that some of these findings may be unique to RA, and extrapolation to non-Ra individuals may be limited. “

When Rishi J. Desai, PhD, assistant professor at Brigham and Women’s Hospital, said that “Superior PhD, at Brigham and Women’s Hospital, said that” Superior PhD, in commenting on the results of the study. to explain the results obtained. It deserves further investigation and replication in diverse populations. He added: “It is worth noting that a key challenge in evaluating this hypothesis using insurance claims data is the unavailability of some important factors such as socioeconomic status and patient frailty.” This may be driving treatment choices between conventional DMards, which are less expensive with benign versus benign. Side effects and biologic or targeted DMards, which are more expensive with more favorable adverse events. “

Previous studies

Several studies have examined the effect of DMARDs, including BDMARDs such as tumor necrosis factor inhibitors, on dementia in patients with RA.

Among these studies is a study by Desai and colleagues that looked at the comparative risk of AD and related dementias in 22,569 Medicare beneficiaries who received tofacitinib (a JAK inhibitor), tocilizumab (an IL-6 inhibitor), or TNF inhibitors compared with abatacept (a T-cell activation inhibitor). No distinct risk associations were found in this cohort study.

Other previous studies include:

  • A study of about 21,000 patients with RA and a non-RA cohort of about 62,000 found a 37% reduction in the development of dementia among RA patients treated with DMARDs. The effect was dose-dependent, greater with high cumulative doses, and was found in both men and women and in subgroups under and over 65 years of age.

  • A retrospective study of electronic health records from 56 million adult patients identified a subset of patients with RA, psoriasis, ankylosing spondylitis, ulcerative colitis, or Crohn’s disease in whom systemic inflammation increased the risk of AD through a mechanism involving TNF. The risk of AD in patients was reduced by treatment with etanercept, adalimumab, infliximab, or methotrexate, with greater reductions observed in younger patients than in older patients treated with TNF-blockers.

  • A propensity score retrospective cohort study of 2,510 US veterans with RA found that TNF inhibitor use reduced the risk of dementia by 36%, compared with controls (HR, 0.64; 95% CI, 0.52–0.80) and The HR, 0.64; 95% CI, 0.52–0.80) and The HR, and 0.64; 95% CI, 0.52–0.80) and HR, 95% CI, 0.52–0.80) and HR, 95% CI, 0.52–0.80) and HR, 95% CI, 0 .52–0.80) and HR, 95% CI, Effects were consistent 5–20 years after RA diagnosis.

  • In a retrospective, multinational, matched, controlled study of patients older than 50 years with RA, previous methotrexate use was associated with a lower risk of dementia (OR, 0.71; 95% CI, 0.52-0.98). Methotrexate use for more than 4 years showed the lowest risk of dementia (odds ratio, 0.37; 95% CI, 0.17-0.79).

These previous studies, Sattui and colleagues noted, have many flaws, including case designs, different definitions of exposure or outcomes, and inadequate control of confounders, highlighting the need for more rigorous research.

Several authors of the CMS-required study reported research support, grants, and consulting fees from pharmaceutical companies. The research was supported by a grant from the National Institutes of Health. Desai reported receiving funding from the National Institute on Aging for Medicines to replicate dementia research.

This article originally appeared on, part of the Medscape Professional Network.

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